A first-in-human, phase 1 study of the SHP2 inhibitor PF-07284892 as monotherapy and in combination with different targeted therapies in oncogene-driven, treatment-resistant solid tumors.
Authors: Alexander E. Drilon, Melissa Lynne Johnson, Shirish M. Gadgeel, Dale Nepert, Gang Feng, Marzieh Golmakani, Micaela Reddy, Allison Harney, Colleen Oliver, Bethany Mills, Judy Therond, S. Michael Rothenberg, Manish Sharma, Timothy A. Yap
Journal: Journal of Clinical Oncology (2023)

3020 Background: Src homology region 2 domain-containing phosphatase-2 (SHP2) activation mediates targeted therapy resistance in various oncogene-driven cancers. In this phase 1 study (NCT04800822), the novel SHP2 inhibitor PF-07284892 (ARRY-558) was evaluated alone and in combination with different targeted therapies in patients (pts) with oncogene-driven tumors that progressed on prior targeted therapy. Unlike other phase I studies, the unique design of this trial allowed pts to receive combination therapy during dose escalation after a period of PF-07284892 monotherapy. This is critical given that monotherapy efficacy was deemed unlikely based on preclinical data. Methods: Eligible pts with advanced solid tumors were enrolled into escalating dose cohorts of PF-07284892 monotherapy. In the absence of dose limiting toxicity (DLT), matched targeted therapy (lorlatinib for ALK/ROS1 fusion+ cancers, encorafenib + cetuximab for BRAF V600E colorectal cancers, and binimetinib for MAPK-mutant cancers) could be added after 6 weeks of monotherapy at the discretion of the investigator. Primary objectives were safety, tolerability, and recommended dose for further evaluation (RDE) determination. Secondary/exploratory objectives included analyses of pharmacokinetics (PK), circulating tumor DNA (ctDNA), and monotherapy/combination therapy objective response (RECIST v1.1). Results: As of 9/19/2022, 33 pts with oncogene-driven solid tumors were enrolled (20-80 mg, orally twice weekly, day 1 and 4 or day 1 and 2 schedule), of whom 18 received combination therapy (5 ALK/ROS1 fusion+ cancers, 4 BRAF V600E + CRCs, 9 MAPK mutant cancers). The median age was 54.5 y (range 32-78). The most common treatment-related adverse events (TRAEs; &gt;15%) for monotherapy were anemia (21%), peripheral edema (18%), and increased AST (18%). Cycle 1 monotherapy DLTs occurred in 4 pts: G3 increased AST, ALT, and bilirubin (n=1); anemia (n=1); and increased AST and ALT, and thrombocytopenia (n=1); and G4 bilirubin (n=1). PF-07284892 PK was dose proportional. 40 mg twice weekly (day 1 and 2) was selected as the RDE. With combination therapy, confirmed RECIST v1.1 partial responses (PR) were observed in 3 treatment-refractory pts (2 lorlatinib and 1 binimetinib combination), and stable disease was observed in 6 treatment-refractory pts. ≥80% ctDNA founder mutation reduction was observed post combination therapy initiation in 2 of the responding pts. Conclusions: PF-07284892 was generally well tolerated alone and in combination with rational targeted therapies. This study design enabled combination therapy rescue of disease progression on PF-07284892 monotherapy with 3 pts achieving confirmed PR. Clinical trial information: NCT04800822 .